The major objective of this project is to determine host and viral factors which influence murine resistance to rabies virus. It has been shown that resistance to intraperitoneally (i.p.)-inoculated street rabies virus (SRV) was under genetic influence. Testing of second backcross progeny has confirmed that two genes controlled susceptibility if the first backcross parent had been selected for resistance to SRV and both parents were of similar H-2s haplotype. If the parents were of different H-2 haplotypes, or the first backcross parent was randomly selected, different combinations of 1-4 segregating genes appeared to be involved. This secondary influence of H-2 was not obvious in earlier studies with inbred strains and F1 hybrids. Additional genetic studies have indicated that SRV resistance genes of SJL/J and CBA/J mice were allelic (identical). Pathogenesis studies have shown that 5 days after i.p. inoculation SRV entered the spinal cord of resistant and susceptible mice in the thoracic area, probably along splanchnic nerves of the sympathetic nervous system. Following entry into the thoracic area, SRV ascended to the cervical area of the cord and then the brain. Minimal concentrations of virus were detected in the lumbar area. There was minimal replication of SRV in spinal cord and brain of resistant SJL and CBA mice. In contrast, virus concentrations were 99% greater in CNS tissues of susceptible mice as compared to resistant mice which developed clinical disease but survived. Serum neutralizing antibody appeared earlier and the titer was 100- to 1,000-fold greater in resistant SJL and CBA as compared to susceptible mice. DBA/2 mice, however, which survived after onset of clinical disease, had neutralizing antibody titers similar to susceptible strains. Studies of immunoglobulin isotypes have indicated there was a higher concentration of Gamma2a in sera of uninfected resistant SJL as compared to susceptible A/WySn mice. Immune function defects are being introduced into resistant mice to help elucidate the reasons for susceptibility differences to SRV.